Other APPs
The usefulness of individual APP measurement in diagnosis of inflammatory disease varies by species (Table 26.2). The following APPs have proven utility in one or more large animal species.
HAPTOGLOBIN. When haptoglobin enters the circulation, it immediately binds hemoglobin to form a complex that is then internalized by hepatic Kupffer cells.44 Increased haptoglobin during the acute phase response occurs due to transcriptional activation. Haptoglobin may regulate and modulate the immune response during inflammation.45 Serum haptoglobin concentration increased in experimentally induced bacterial placentitis in mares and experimentally induced strongyle infections of young horses.46,47 Both acute and chronic heaves correlated with increased serum haptoglobin following allergen challenge.48 Interestingly, in one study haptoglobin concentration decreased in serum but increased in peritoneal fluid in horses with colic.49 Serum haptoglobin concentration increases in the first week postpartum in dairy cows.50 Measurement of haptoglobin in milk is superior to measurement in serum for diagnosis of mastitis, although serum measurement is also useful.22,51 Haptoglobin performs well as an acute phase marker in sheep, with increases found during inflammatory diseases including bacterial metritis and pneumonia.52,53 Serum haptoglobin concentration varies with reproductive status in goats: Pregnant does in the second trimester have decreased values, and lactating does have increased values when compared to open, nonlactating does.54
C-REACTIVE PROTEIN (CRP). In health, CRP is present in trace amounts in circulation. Inflammation and tissue necrosis can markedly upregulate CRP levels.55 The role of CRP in the acute phase response may be clearance of endogenous or exogenous substances (e.g., microorganisms, cellular debris), but CRP may also worsen inflammatory tissue damage via complement activation.56 Dairy cattle had increased serum CRP levels during lactation that were highest at peak lactation and declined thereafter; mastitis and other inflammatory diseases caused further increases (e.g., a threefold increase in CRP levels in mastitic cows compared to healthy lactating cows).57 Increased CRP has been associated with pneumonitis, enteritis, and arthritis in horses.58
SERUM AMYLOID A (SAA).
The SAA protein family of apolipoproteins includes both constitutively expressed proteins and acute phase reactants that are markedly upregulated during inflammation.59 The induced proteins chemotactically recruit leukocytes and are implicated in the pathogenesis of chronic inflammation, as they are precursors of the amyloid A protein in amyloidosis. SAA testing via point-of-care handheld devices has become standard practice in some equine facilities. Studies support the use of SAA measurement as an indicator of acute inflammation (including septic inflammation and heaves) and a useful monitoring tool for clinically ill horses, with diagnostic accuracy often superior to that of total white blood cell (WBC) count, fibrinogen, and/or A/G ratio.46,48,60-62 In one study systemic inflammation in horses caused substantial increases in SAA compared to local inflammation, and a cutoff value of greater than 10 mg/L yielded sensitivity of 82% and specificity of 71% in differentiating inflammatory from noninflammatory disease in horses.62 SAA concentration in both serum and peritoneal fluid increased in horses with colic.49 In contrast, experimental strongyle infection failed to elicit an increase in serum SAA concentration.47 SAA has demonstrated prognostic value in horses with colic but was not useful as a prognostic marker in general inflammatory disease when used as a single measurement.63,64 As with haptoglobin, SAA increases in the first postpartum week in dairy cows, and measurement of milk SAA levels is superior to serum levels to diagnose mastitis, although both are useful.22,50,51APOLIPOPROTEIN A1 (APO A1). Apo A1 is a negative acute phase reactant in humans and domestic animals. Apo A1 is associated with high-density lipoproteins. A role as a constitutive antiinflammatory factor has been posited for Apo A1.65
CERULOPLASMIN (CP). CP plays a key role in iron metabolism, and CP-bound copper accounts for 95% of plasma copper concentration.
CP interacts with several proteins, including ferritin, neutrophil myeloperoxidase, and lactoferrin.66 Equine serum CP concentration increases with sterile inflammation and surgical manipulation. Transient changes in serum CP concentration occur in mares immediately before and after foaling.67α2-ANTIPLASMIN (α2-AP). α2-AP is a fibrinolytic inhibitor via its specific inactivation of plasmin. Measurement of increased plasmin α2-AP complexes is one indicator of fibrinolysis. α2-AP increases in horses with colic, as does plasminogen, and therefore 3068
may have utility as an acute phase biomarker.,
PIG MAJOR ACUTE PHASE PROTEIN (PIG-MAP, ALSO ITIH4). Pig-MAP is the porcine homolog of a human kallikrein- sensitive protein and is a useful indicator of inflammatory diseases.69,70 The related proteins in humans, pigs, and rats have been designated collectively as ITIH4, a new member of the inter-alpha-trypsin inhibitor (ITI) protein family with unknown biological function. The utility of ITIH4 as an acute phase reactant in cattle is also described.71
FERRITIN. Ferritin is an iron storage and transport protein. Ferritin levels can markedly increase during infectious and other inflammatory disorders, presumably to sequester iron and limit availability to microbes.72 Species-specific assays are generally needed to measure ferritin. An equine-specific assay is available and has some cross-reactivity with other species.73 Ferritin has
shown usefulness as a biomarker in horses. Strenuous exercise also causes an increase in ferritin that persists for up to 2 days.74
α1-ACID GLYCOPROTEIN (α1-AG). Also known as orosomu- coid, α1-AG is a carrier of basic substances, including therapeutic drugs and steroids. Increased α1-AG values have been found in cattle with various inflammatory disorders, including mastitis and traumatic pericarditis.75